Cerebral edema, an increase in brain tissue water content, is responsible for significant morbidity and mortality in many different disease states, including traumatic brain injury (TBI), stroke, infection, tumor, and a host of chemical and metabolic intoxications. The two types of cerebral edema are vasogenic edema and cytotoxic (cellular) edema. Vasogenic edema is characterized by the disruption of the blood-brain barrier (BBB) and may be caused by direct injury or by breakdown of the BBB (e.g., by tumors). BBB disruption leads to the accumulation of blood components in the brain and an influx of water into the interstitial space between cells follows, causing swelling of the tissue. Cytotoxic edema is characterized by the flux of water into brain cells (predominantly brain glial cells) and is associated with trauma, ischemia and toxins.
Glial cells have compensatory mechanisms to restore water homeostasis across the cellular membrane, but following injury these mechanisms may be disrupted. TBI is characterized by mixed cytotoxic and vasogenic edema mechanisms, both contributing to overall cerebral edema. After TBI, glial cells swell [1] due to changes in the extracellular pH and concentrations of ions, including potassium, sodium, and chloride[2]. The resulting cytotoxic edema combines with the vasogenic edema caused by direct BBB injury. Reduced blood flow to the affected brain area (cerebral ischemia) leads to further ion shifts and cytotoxic edema. A vicious cycle involving components of both types of edema can proceed until the brain swells uncontrollably resulting in permanent brain damage or death. A treatment aimed at breaking the edema cycle and restoring normal ion and protein homeostasis within the extracellular space would be ideal at reversing cerebral edema and brain swelling following TBI.